NK cell exhaustion in VEXAS: another piece in the puzzle Free

In this issue of Blood, Breillat et al¹ describe a profound impairment in natural killer (NK) cell function in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, shedding light on how innate immune exhaustion contributes to its complex inflammatory phenotype.

Since its initial description,² VEXAS syndrome has stood out as a prototypical hematoinflammatory disorder linking acquired somatic mutations in UBA1 to systemic inflammation and hematological abnormalities. Although the role of myeloid cells in driving inflammation has been well described,³ the contribution of cytotoxic lymphocytes has remained relatively understudied.

Employing a multifaceted approach that includes phenotypic, transcriptomic, and functional assessments, Breillat et al provide compelling evidence of a striking dysfunction in NK cells among patients with VEXAS syndrome.¹ The rationale for investigating the role of NK cells in VEXAS syndrome stems from the clinical observation that, beyond its broad spectrum of inflammatory and hematological manifestations, patients appear particularly prone to severe infections, including bacterial, viral, fungal, and mycobacterial. Notably, atypical infections with Legionella pneumophila and Pneumocystis jirovecii are particularly common in VEXAS syndrome. These infections can occur despite appropriate prophylaxis, and even in the absence of immunosuppressive therapy, suggesting the presence of an underlying, intrinsic immune defect associated with VEXAS syndrome.^4,5 

Breillat et al performed an in-depth immunophenotyping of peripheral NK cells in a cohort of 40 patients with VEXAS syndrome, 22 patients with autoinflammatory syndromes without UBA1 mutations, and 16 age- and sex-matched healthy controls.¹ Using cytometry by time-of-flight, single-cell RNA sequencing (scRNAseq), whole blood stimulation assays, and in vitro cytotoxicity tests, they found that NK cells in patients with VEXAS syndrome are numerically and functionally impaired. Specifically, there was a reduction in mature CD56^dimCD16⁺ NK cells, expansion of CD56^brightCD16^– subsets, and evidence of exhaustion phenotypes with increased PD-1 expression and decreased cytotoxic markers (NKp46, CD8α). Single-cell RNA sequencing (scRNAseq) confirmed a downregulation of cytotoxicity and cytokine production (IL-2, IFN-γ) signatures, which occurred in parallel with an enhancement of proinflammatory programs. Subsequent functional assays revealed impaired cytokine responses upon toll-like receptor stimulation and reduced IFN-γ production. In vitro exposure to UBA1 inhibitors recapitulated key defects, including reduced cytotoxic capacity and increased cell death. Notably, low peripheral NK cell counts were associated with a higher risk of severe infections, independent of steroid dose and CD4⁺ and CD8⁺ T lymphocyte counts. Collectively, these findings support the hypothesis that reduced NK cell number and function are pivotal contributors to infectious susceptibility in VEXAS syndrome.

These findings expand the current understanding of the pathophysiology of VEXAS syndrome. NK cell exhaustion adds a layer to the disease’s immunological complexity, indicating that the UBA1-mutant hematopoietic clone undermines immune function not only through excessive cytokine production by myeloid cells but also through functional impairment of the innate cytotoxic compartment. This observation may offer a potential explanation for the high incidence of severe infections observed in patients with VEXAS syndrome, which has been previously attributed to the use of immunosuppressive therapy or neutropenia. In contrast, the data presented by Breillat et al suggest that an immunological defect in NK cells might be implicated. Accordingly, prospective monitoring of the NK cell immunophenotype in VEXAS syndrome (ie, increased expression of exhaustion markers and decreased expression of cytotoxicity markers) might be relevant to disease prognosis and therapeutic intervention.

A key question remains unanswered: how precisely do UBA1 mutations in hematopoietic precursors lead to NK cell dysfunction? Interestingly, NK cells from VEXAS syndrome patients harbor the UBA1 mutation,⁶ suggesting a potential cell-intrinsic effect of dysregulated ubiquitination on the survival and function of these cells. It is also possible that NK cell defects in VEXAS syndrome are an indirect consequence of chronic systemic inflammatory milieu generated by UBA1-mutant myeloid cells.⁷ In addition, given the high frequency of somatic DNMT3A and TET2 mutations observed in VEXAS syndrome,⁸ it will be important to understand how co-occurring mutations differentially shape NK cell dysfunction. Longitudinal studies in patients and investigation of experimental models will be needed to explore these aspects.³ 

The work of Breillat et al also introduces the intriguing idea of therapeutically reversing NK cell exhaustion as a potential strategy to prevent or treat severe infections in VEXAS syndrome. In line with novel immunotherapy approaches in oncology,⁹ interventions such as IL-15 superagonists or inhibitory receptor blockade might restore NK function in patients with VEXAS syndrome, and therefore deserve exploration in preclinical models. In summary, the study of Breillat et al significantly advances our understanding of the immunopathology of VEXAS syndrome by positioning NK cells, and their dysfunction, as central players in disease biology and susceptibility to severe infection. Beyond the management of inflammation, the restoration of immune competence may represent the next frontier in the treatment of VEXAS syndrome.

Conflict-of-interest disclosure: The authors declare no competing financial interests.